Circulating plasma cells (either polyclonal or monoclonal) as markers of aggressive Multiple Myeloma phenotype

Multiple myeloma (MM) is a hematological neoplasm characterized by the clonal proliferation of malignant plasma cells (PCs) in the bone marrow (BM). The pathogenesis of MM is complex and multifactorial, with significant heterogeneity among patients, making risk stratification and disease monitoring difficult, often based on invasive sampling. Therefore, there is growing interest in less invasive methods such as liquid biopsy. In this study, the potential of circulating plasma cells (CPCs), including polyclonal CPCs, was evaluated as innovative biomarkers for risk stratification in 107 MM patients. Using multiparametric flow cytometry, the phenotypes of the CPCs in peripheral blood (PB) were analyzed, finding their presence in 92% of cases (monoclonal CPCs 77%, polyclonal CPCs 15%), with a median of 0.02% (range 0.002-9%). CPCs were significantly correlated with various biochemical parameters and the percentage of BM-PCs (p<0.05), indicating an association with a more aggressive phenotype even in the presence of polyclonal PCs. Genomic analyses identified recurrent mutations in key genes ( KRAS and NRAS ), potentially involved in CPCs formation. Notably, high CPCs-patients had mutation restricted to KRAS , while patients with a low amount of CPCs carried solely NRAS mutations. Lastly, comparisons between PC phenotypes in BM and PB showed significant heterogeneity, such as light chain inversion or variations in the expression of markers like CD56 and CD138, suggesting the presence of clonal heterogeneity and potential migratory predisposition. Such differences might have prognostic and therapeutic implications, and might contribute to the emergence of CPCs.